Background In Parkinson’s disease, converging evidence supports a pathogenic role for excessive α–synuclein accumulation in synaptic terminals that may propagate back to the soma of vulnerable nerve cells ... [more ▼]

Background In Parkinson’s disease, converging evidence supports a pathogenic role for excessive α–synuclein accumulation in synaptic terminals that may propagate back to the soma of vulnerable nerve cells such as neurons in the substantia nigra pars compacta. The resulting loss of dopaminergic terminals in the striatum can be demonstrated in vivo using 18F-Dopa-PET (positron emission tomography). However, there’s currently no validated biomarker of the progressive synaptic dysfunction in other vulnerable areas such as the cerebral cortex. Goal In this longitudinal study, we will test the hypothesis that the loss of synaptic terminals in a mouse model of excessive α–synuclein accumulation can be demonstrated in vivo before the occurrence of behavioural disturbances using 18F-UCB-H, a new PET biomarker developed at CRC. We will also test if this new imaging modality is sensitive enough to study the effect of a disease modifying therapy such as chronic physical exercise. Methods We will use microPET for the in vivo quantification of 18F-UCB-H brain uptake in 16 wild type animals and 16 transgenic (Tg) mice overexpressing human α–syn under the mThy1 promotor every 2 months. Data will be validated against post-mortem analyses after the last PET study. Predictions We predict decreased tracer uptake over time in the basal ganglia and cerebral cortex in Tg mice as compared with WT animals. Also, we predict a relationship between 18F-UCB-H uptake levels in basal ganglia and cerebral cortex and progressive alterations in both motor and cognitive functions, respectively. Further, we also expect that chronic exercise will slow down both motor and cognitive disturbances, as well as the rate of 18F-UCB-H brain uptake decreases. Conclusion If 18F-UCB-H PET proves to be a valid biomarker for the early detection of α–synuclein accumulation in the pre-clinical model of PD, the methods will tested on human clinical populations. [less ▲]

Pathologies affecting the striatum (e.g., Parkinson’s and Huntington’s disease) can result in impaired habit learning abilities. Likewise, such impairments have also been observed after stroke affecting ... [more ▼]

Pathologies affecting the striatum (e.g., Parkinson’s and Huntington’s disease) can result in impaired habit learning abilities. Likewise, such impairments have also been observed after stroke affecting the middle cerebral artery territory (encompassing the striatum). However, habit learning has never been investigated in animal stroke models, for which it could be a reliable measure of cognitive deficits. We thus assessed the ability to learn a habitual sequence of lever-presses using operant conditioning in mice after MCAO, one of the most common stroke models. C57Bl/6J mice underwent MCAO or sham surgery. Sensorimotor functioning was assessed using the vertical pole test, rotarod and amphetamine-induced rotation test. Habit learning was evaluated using the operant serial order learning (SOL) task: mice had to perform a series of two consecutive lever-presses (i.e., left then right) to obtain a food reward. Lesion extents were finally determined using anti-NeuN immunohistochemistry. MCAO mice were significantly impaired in both the rotarod and vertical pole test, and displayed a significantly greater number of ipsilateral rotations after amphetamine administration. In the operant SOL task, MCAO committed more errors than sham; moreover, they did not show any significant increase in performance along the sessions. Histological analysis showed consistent striatal and cortical infarctions. The lack of habit learning ability in MCAO mice is congruent with both the literature investigating the effect of striatal lesion in animals and the symptomatology observed in human stroke patients. Habit learning could thus be regarded as a reliable measure of functional outcome after MCAO, in combination with test assessing sensory and motor aspects. [less ▲]

Nowadays, no suitable animal model exists to assess long-term disabilities after cerebral ischemia. The aim of this study was to compare long-term behavioral and histological differences between two ... [more ▼]

Nowadays, no suitable animal model exists to assess long-term disabilities after cerebral ischemia. The aim of this study was to compare long-term behavioral and histological differences between two common mouse strains (129S2/SvPasCrl and C57BL6H) after 30 minutes of middle cerebral artery occlusion (MCAo). Sensorimotor assessments were conducted at one and at three weeks post-surgery using accelerated Rotarod and open-field locomotion. Long-term behavioral testing began four weeks after MCAo using operant conditioning in a progressive fixed-ratio (FR) schedule. Experiments ended with volumetric determination of the infarcted area using NeuN immunostaining. Although no effect of ischemia was detected in 129S2 mice using these tests, in C57 mice, results showed obvious short-term motor and locomotor deficits. Furthermore, subtle but persistent disturbances of endurance and executive functioning were recorded by the progressive schedule tests but not highlighted by sensorimotor tests. Ischemic lesion extended to the dorsolateral part of the striatum in both strains and recurrent cortical damages were also observed in C57 mice. All those results are in accordance with inherent morphological and behavioral features of each strain. Since the motor cortex is spared by 30 minutes MCAo, functional disabilities could be related to striatal damages. In conclusion, C57BL/6H mouse strain, by offering an acceptable survival rate and enough sensitivity to MCAo, seems to be a mouse strain suitable to evaluate long-term deficits and possible functional recovery after cerebral ischemia. [less ▲]

Excitatory or inhibitory conditioning processes have been proposed to account for the context-dependent establishment of amphetamine psychomotor sensitization in rodents. The purpose of this study was to ... [more ▼]

Excitatory or inhibitory conditioning processes have been proposed to account for the context-dependent establishment of amphetamine psychomotor sensitization in rodents. The purpose of this study was to test the predictions of these theories in mice. We first assessed the consequence of the extinction of post-sensitization conditioned activity (CR) on the ulterior expression of sensitization. We also assessed the relations between several measures of sensitization and conditioned hyperactivity revealed on a saline challenge using simple and multiple regression analyses. Context-dependent sensitization was induced via 7 amphetamine injections in the test context given alternately with 7 saline injections in another context in paired mice, unpaired mice receiving the converse pretreatment. Context-dependent sensitization (drug challenge) and the CR (saline challenge) were revealed subsequently. After CR extinction (over 7 every-other-day repetition of the saline challenge), mice were tested again for context-dependent sensitization. Against the excitatory conditioning model, CR extinction spared context-dependent sensitization in paired mice, and regression analyses revealed no significant correlations between the size of the CR and several measures of sensitization. In apparent agreement with the inhibitory conditioning model, unpaired mice expressed higher levels of sensitization in the test context after extinction than before. However, regression analyses did not indicate that activity on the saline challenge was related to measures of sensitization in unpaired mice. Therefore, the present results support neither the excitatory nor the inhibitory conditioning models of context-dependent sensitization, but remain compatible with theories proposing that other inhibitory mechanisms modulate sensitization. [less ▲]

In this study, we examined a number of short and long-term sensorimotor, behavioural and cognitive consequences of an experimental ischemia induced by a 60-min right middle cerebral artery occlusion (MCAO ... [more ▼]

In this study, we examined a number of short and long-term sensorimotor, behavioural and cognitive consequences of an experimental ischemia induced by a 60-min right middle cerebral artery occlusion (MCAO) in 129S2 mice. During 14 days after surgery, a classical sensorimotor assessment was conducted using hanging wire test, negative geotaxis test, grip strength test, accelerated rotarod test and locomotor activity-meter. In order to provide a technique for the assessment of more resistant consequences of ischemia on fine psychomotor control, the peak procedure (a modified version of the operant fixed-interval schedule of reinforcement) was used. This procedure also helped to objectify temporal perception in mice five weeks following surgery. On several sensorimotor tests, ischemic mice showed some degree of impairment which rapidly tended to improve after stroke, a profile of results substantially consistent with previous studies. Five weeks post-surgery, ischemic mice tested with the peak procedure exhibited a moderate but yet significant temporal regulation impairment along with a reduced response rate compared to control mice. The present results suggest that the peak procedure and other derived operant schedules of reinforcement may provide useful and sensitive tools for the long-term assessment of both behavioural and cognitive aspects of the consequences of an experimental ischemia. [less ▲]

It has been hypothesised that a leftward shift in the response distribution obtained in the peak interval (PI) procedure is a characteristic of cognitive enhancement in which mental processes are speeded ... [more ▼]

It has been hypothesised that a leftward shift in the response distribution obtained in the peak interval (PI) procedure is a characteristic of cognitive enhancement in which mental processes are speeded. Metrifonate, a cholinesterase inhibitor with reported cognitive enhancing properties in many animal models of learning and memory, was tested in the PI procedure. Acute administration of 3 and 60 mg/kg but not 1 and 30 mg/kg in fully trained rats shifted the response distribution to the right, whereas subchronic administration of 10, 30 or 50 mg/kg during task acquisition had no effect on timing behaviour. On the basis of the present data, it can be concluded that the effects of a cognition enhancer in the PI procedure cannot be predicted from the scalar expectancy theory (SET). Furthermore, SET does not appear to be an appropriate tool for analysing the acquisition of timing behaviour. (C) 2003 Elsevier B.V/ECNP. All rights reserved. [less ▲]

This paper first provides a survey of the expanding brain imaging literature in the field of time processing. showing that particular task features (discrete vs rhythmic, perceptual vs motor) do not ... [more ▼]

This paper first provides a survey of the expanding brain imaging literature in the field of time processing. showing that particular task features (discrete vs rhythmic, perceptual vs motor) do not significantly affect the basic pattern of activation observed. Next, positron emission tomography (PET) data obtained in a timing task (temporal reproduction) with two distinct duration ranges (2.2-3.2 and 9-13 s) are reported. The stimuli consisted of vibrations applied to the subject's right middle finger. When the vibration ended, the subject estimated an interval identical to its length before pressing a response button. The control task used cued responses with comparable intervals and stimuli, The pattern of activation obtained in the timing task as compared to control mainly included areas having attentional functions (the right dorsolateral prefrontal, inferior parietal, and anterior cingulate cortices), and the supplementary motor area (SMA). No significant difference was seen as a function of the duration range. It is argued, firstly. that involvement of the attentional areas derives from specific relations between attention and the temporal accumulator, as described by dominant timing models. and, secondly, that the SMA, or more probably one of its subregions, subserves time processing [less ▲]

Wood mice (Apodemus sylvaticus) and OF1 albino mice (Mus musculus) were compared over durations ranging from 0.5 to 7 s, using the differential reinforcement of response duration schedule (DRRD) and a 'platform' response, i.e. staying on a small platform for a specified criterion duration to be reinforced. Species-related differences were found for mean response durations, efficiency and the number of trials needed to reach a preset performance criterion. Coefficients of variation of response durations did not differ. Overall, OF1 mice needed more trials than wood mice to reach a temporal criterion. However, over 3-7 s, data from both strains almost fitted the behavioral assumptions of Scalar Timing theory. Performance of mongolian gerbils (Meriones unguiculatus) trained in a similar setting was shown for visual comparison. [less ▲]

For all intents and purposes, catastrophic interference, the sudden and complete forgetting of previously stored information upon learning new information, does not exist in healthy adult humans. But does ... [more ▼]

For all intents and purposes, catastrophic interference, the sudden and complete forgetting of previously stored information upon learning new information, does not exist in healthy adult humans. But does it exist other animals? In light of recent research done by McClelland, McNaughton, [less ▲]

Positron emission tomography (PET) data were obtained from subjects performing a synchronization task (target duration 2700 ms). A conjunction analysis was run to identify areas prominently activated both in this task and in a temporal generalization task (target duration 700 ms) used previously. The common pattern of activation included the right prefrontal, inferior parietal and anterior cingulate cortex, the left putamen and the left cerebellar hemisphere. These areas are assumed to play a major role in time processing, in relation to attention and memory mechanisms. [less ▲]